Next-generation antibody (NGA) therapeutics with antibody architecture modifications represent a key area of monoclonal antibody (mAb) research and development. Oncology is the main focus, with about 50% of the oncology mAb pipeline consisting of NGAs. Syed, B. A., et al., Next-Generation Antibodies, Nature Reviews Drug Discovery, 13:413 (2014).
Antibody-drug conjugates (ADCs), the most prominent of the new antibody technology platforms, generally comprise a cytotoxic agent attached to a mAb via chemical linkers. By offering targeted delivery of chemotherapeutic agents directly to the cancerous tissue, ADCs may increase the clinical efficacy of mAbs and enable the deployment of cytotoxins that are too potent for systemic administration. The first ADC product, gemtuzumab ozogamicin (MYLOTARG®; Wyeth), a calicheamicin-linked CD33-specific mAb for the treatment of acute myeloid leukaemia (AML), was approved in 2000 but withdrawn in 2010 over safety concerns. New platforms for ADC development, such as the targeted antibody payload platform (TAP; Seattle Genetics and ImmunoGen), have emerged. In late 2011, brentuximab vedotin (ADCETRIS®; Seattle Genetics), a CD30-specific mAb linked to the antimitotic agent monomethyl auristatin E (MMAE) for the treatment of non-Hodgkin's lymphoma (NHL), became the first of the new ADCs to gain approval from the US Food and Drug Administration (FDA). The second approval was ado-trastuzumab-emtansine (KADCYLA®; Genentech/Roche) in early 2013. Ado-trastuzumab-emtansine and the mAb pertuzumab (PERJETA®; Roche (approved in 2012)) were developed as line-extensions of trastuzumab (HERCEPTIN®; Roche), targeting HER2 (also known as ERBB2) with different modes of action; PERJETA® inhibits HER2-HER3 dimerization whereas ado-trastuzumab-emtansine delivers a cytotoxic payload to the cells.
Cytotoxic molecules, radionuclides, and certain chemotherapeutic drugs have been chemically linked to monoclonal antibodies that bind tumor-specific or tumor-associated cell surface antigens. See, e.g., International (PCT) Patent Application Nos. WO 00/02587, WO 02/060955, WO 02/092127; and, U.S. Pat. Nos. 8,198,417, 8,012,485, 5,475,092, 6,340,701, and 6,171,586.
Existing mAb development processes routinely make use of techniques such as hinge engineering and affinity maturation. However, a challenge remains to improve the efficacy and minimize the undesirable side effects of immunoconjugate therapy.